Dermal compositions

ABSTRACT

Disclosed herein are veterinary compositions including imidacloprid or an analogue thereof; a pyrethroid; a solvent selected from the group consisting of N-methyl pyrrolidone, N-ethyl pyrrolidone and mixtures thereof; and dimethyl sulfoxide. The veterinary compositions of the invention are useful in methods of controlling parasites on or within warm-blooded domesticated animals.

The present invention relates to composition for treating parasites, inparticular ticks and fleas, on an animal, in particular a dog.

Advantix® is a commercially available product which is marketed as beingeffective in treating ticks, flies and mosquitoes on a dog. It comprisesboth imidacloprid and permethrin as active ingredients and itsformulation is described in U.S. Pat. No. 7,728,011. Advantix® istypically administered as a spot-on composition and the characteristicsof the composition are such that it then spreads across the skin of theanimal. In order to achieve this, while the action of the composition isnot systemic, it is important that the composition penetrates through tothe lower dermal layers.

While Advantix® has been demonstrated to be effective in the long term(i.e. over a period of 3 to 4 weeks) control of parasites on animals, inparticular dogs, it suffers from the problem that the primary solventwith which it is formulated, N-methyl pyrrolidone (NMP), is a high risksolvent. More specifically, following the recent re-examination by the31st Committee on the Adaptation to Technical Progress (31st ATP), ofthe EU directives for the elimination of technical barriers to tradewith dangerous substances and preparations and, in accordance with EUdirective 2009/2/EC dated 15 Jan. 2009, NMP is now classified as toxic(T classification) and reprotoxic of category 2 in the Risk-Phrasal R61.This means that it is considered to be teratogenic and so presents ahandling risk during formulation. Similarly, it has been categorised asa class 2 solvent by the FDA.

The safety problem associated with NMP is well-documented and there hasbeen a drive to identify an alternative safer solvent (see, for example,EP 2266400). In this regard, there have been various suggestionsregarding an appropriate substitute but, because NMP is so effective atdissolving polar materials and their salts, it has proven difficult toidentify an equivalent alternative. This is particularly a challenge inthe formulation of a veterinary composition, where an alternativesolvent needs to be identified without having any negative impact on theefficacy of the composition. This situation is further complicated wherethe composition includes more than one active ingredient.

SUMMARY OF INVENTION

Against this background, it is clear that there is a need for aveterinary composition which is as effective as commercially availableproducts, such as Advantix®, but which does not suffer from the safetyproblems associated with using NMP as the sole primary solvent. Withthis in mind, the present inventor has investigated the use ofalternative solvents.

However, despite indications to the contrary in various references, theapplicant has surprisingly found that it is not possible to simplysubstitute a solvent indicated to be an alternative to NMP for NMP andstill obtain a composition which is suitable for veterinary uses, evenwhere the solvent has been specifically described as an alternative toNMP for formulating imidacloprid. An example of such as solvent isArmid® FMPC which is specifically marketed as an alternative to NMP forthis very purpose. Without wishing to be bound by theory, it is believedthat this is because the compositions with which the present inventionis concerned comprise a combination of active ingredients, only one ofwhich is imidacloprid and it is the presence of these further activeingredients which complicates the situation.

The present inventor has identified compositions which comprise bothimidicaloprid and permethrin which can be formulated with less NMP thancommercially available compositions and which surprisingly exhibitimproved long term storage stability under low temperature conditions.

Accordingly, the present invention provides a veterinary compositionwhich comprises imidacloprid or an analogue thereof, permethrin anddimethyl sulfoxide (DMSO). More specifically, the present inventionprovides a veterinary composition comprising;

-   -   0.1 to 20% by weight of imidacloprid or an analogue thereof; and    -   0.1 to 75% by weight of a pyrethroid;        wherein the balance of the composition by weight comprises a        first solvent selected from the group consisting of N-methyl        pyrrolidone, N-ethyl pyrrolidone and mixtures thereof and a        second solvent which is dimethyl sulfoxide (DMSO) and wherein        the composition optionally further comprises:    -   0 to 5% by weight of water;    -   0 to 0.5% by weight of an antioxidant;    -   0 to 2% by weight of at least one organic acid;    -   0 to 2% by weight of pyriproxifen;    -   0 to 40% by weight of further veterinary acceptable        endoparasitic and exoparasitic agents; and    -   0 to 40% by weight of further veterinary acceptable excipients.

In another aspect, the present invention provides a veterinarycomposition comprising;

-   -   0.1 to 20% by weight of imidacloprid or an analogue thereof; and    -   0.1 to 75% by weight of a pyrethroid;        wherein the balance of the composition by weight comprises a        first solvent selected from the group consisting of N-methyl        pyrrolidone, N-ethyl pyrrolidone and mixtures thereof and a        second solvent which is dimethyl sulfoxide (DMSO) and wherein        the composition optionally further comprises:    -   0 to 5% by weight of water;    -   0 to 0.5% by weight of an antioxidant;    -   0 to 2% by weight of at least one organic acid;    -   0 to 2% by weight of pyriproxifen;    -   0 to 40% by weight of further veterinary acceptable        endoparasitic and exoparasitic agents; and    -   0 to 40% by weight of further veterinary acceptable excipients,        wherein the composition comprises less than 20% by weight of        DMSO.

In some embodiments, the veterinary composition comprises less than27.5% by weight of the first solvent. In certain embodiments, theveterinary composition comprises greater than 20% by weight of the firstsolvent.

In another aspect, the present invention provides a veterinarycomposition comprising;

-   -   0.1 to 20% by weight of imidacloprid or an analogue thereof; and    -   0.1 to 75% by weight of a pyrethroid;        wherein the balance of the composition by weight comprises a        first solvent selected from the group consisting of N-methyl        pyrrolidone, N-ethyl pyrrolidone and mixtures thereof and a        second solvent which is dimethyl sulfoxide (DMSO) and wherein        the composition optionally further comprises:    -   0 to 5% by weight of water;    -   0 to 0.5% by weight of an antioxidant;    -   0 to 2% by weight of at least one organic acid;    -   0 to 2% by weight of pyriproxifen;    -   0 to 40% by weight of further veterinary acceptable        endoparasitic and exoparasitic agents; and    -   0 to 40% by weight of further veterinary acceptable excipients,        wherein the composition comprises greater than 20% by weight of        the first solvent.

In one embodiment, the composition comprises less than 20% by weight ofDMSO. In some embodiments, the composition comprises less than 27.5% byweight of the first solvent.

In another aspect, the invention provides a veterinary compositioncomprising:

-   -   0.1 to 20% by weight of imidacloprid or an analogue thereof;    -   0.1 to 75% by weight of a pyrethroid;    -   2.5 to 25% by weight of a solvent selected from the group        consisting of N-methyl pyrrolidone, N-ethyl pyrrolidone and        mixtures thereof;    -   2.5 to 97.3% by weight of dimethyl sulfoxide (DMSO);    -   0 to 5% by weight of water;    -   0 to 0.5% by weight of an antioxidant; and    -   0 to 2% by weight of at least one organic acid.

In some embodiments, the composition comprises less than 20% by weightof DMSO.

In a further aspect, the invention provides a veterinary compositioncomprising:

-   -   0.1 to 20% by weight of imidacloprid or an analogue thereof;    -   0.1 to 75% by weight of a pyrethroid;    -   greater than 20% and up to 25% by weight of a solvent selected        from the group consisting of N-methyl pyrrolidone, N-ethyl        pyrrolidone and mixtures thereof;    -   2.5 to 97.3% by weight of dimethyl sulfoxide (DMSO);    -   0 to 5% by weight of water;    -   0 to 0.5% by weight of an antioxidant; and    -   0 to 2% by weight of at least one organic acid.

In another aspect, the invention provides a veterinary compositioncomprising:

-   -   0.1 to 20% by weight of imidacloprid or an analogue thereof;    -   0.1 to 75% by weight of a pyrethroid;    -   greater than 20% and up to 25% by weight of a solvent selected        from the group consisting of N-methyl pyrrolidone, N-ethyl        pyrrolidone and mixtures thereof; at least 2.5% and 20% by        weight of dimethyl sulfoxide (DMSO);    -   0 to 5% by weight of water;    -   0 to 0.5% by weight of an antioxidant; and    -   0 to 2% by weight of at least one organic acid.

In yet another aspect, the invention provides a veterinary compositioncomprising:

-   -   0.1 to 20% by weight of imidacloprid;    -   0.1 to 75% by weight of a pyrethroid;    -   greater than 20% and up to 25% by weight of a first solvent        selected from the group consisting of N-methyl pyrrolidone,        N-ethyl pyrrolidone and mixtures thereof; and    -   at least 2.5% and less than 20% by weight of a second solvent        which is dimethyl sulfoxide (DMSO).

In some embodiments of any of the preceding aspects, the pyrethroid ispermethrin. In certain such embodiments, the veterinary composition maycomprise permethrin in an amount in the range from 25 to 75% by weight.In particular embodiments, the composition comprises 35 to 67.5% byweight of permethrin. In some embodiments, the composition comprises 2.5to 12.5% by weight of imidacloprid or an analogue thereof.

In some embodiments of any of the preceding aspects, the first solventis N-methyl pyrrolidone.

In some embodiments of any of the preceding aspects, the veterinarycomposition comprises greater than 10% by weight of DMSO (e.g., between10% and 20% DMSO). In certain embodiments, the composition comprisesgreater than 15% by weight of DMSO (e.g., between 15% and 20% DMSO). Inparticular embodiments, the composition comprises greater than 17% byweight of DMSO (e.g., between 17% and 20% DMSO).

In some embodiments of any of the preceding aspects, the veterinarycomposition further comprises an antioxidant in an amount in the rangefrom about 0.05% to about 0.25% by weight. In some embodiments of any ofthe preceding aspects, the veterinary composition further comprises atleast one organic acid in an amount in the range from about 0.05% toabout 1% by weight. In some embodiments of any of the preceding aspects,the veterinary composition further comprises pyriproxifen in an amountin the range from about 0% to about 2% by weight.

Veterinary compositions according to any of the preceding aspects can beused for dermal application. In some embodiments, the veterinarycompositions are pour-on or spot-on formulations.

In certain embodiments of any of the preceding aspects, a veterinarycomposition is designed for use in controlling parasites on or within awarm-blooded domesticated animal. In some such embodiments, parasitesare selected from the group consisting of ectoparasites, endoparasites,or both. In particular embodiments, parasites are selected from one ormore of the groups consisting of fleas, ticks, mites, lice, intestinalworms, heartworms, and other internal worms. Most typically, theparasites are ectoparasites. In some embodiments, the animal is a smalldomesticated animal, such as a dog. In certain embodiments, acomposition is applied dermally to the animal, and may be formulated asa pour-on or spot-on formulation.

The invention also features a method of controlling a parasite on orwithin a warm-blooded domesticated animal. The method involves the stepof applying a veterinary composition of any of the preceding aspects tothe skin of an animal to be treated.

In some embodiments of the method, parasites are selected from the groupconsisting of ectoparasites, endoparasites, or both. In particularembodiments, parasites are selected from one or more of the groupsconsisting of fleas, ticks, mites, lice, intestinal worms, heartworms,and other internal worms. In some embodiments, the animal is a dog.

Ranges provided herein are inclusive unless otherwise specified. Forexample, a composition comprising “0 to 5% by weight of water” maycomprise 0% by weight of water or 5% by weight of water. Ranges providedusing the term “between” are not inclusive. For example, a compositioncomprising “between 2.5% and 20% by weight of DMSO” may not comprise2.5% by weight of DMSO or 20% by weight of DMSO. Such a compositioncould alternatively be described as comprising “greater than 2.5% andless than 20% by weight of DMSO.” Ranges provided using the term “atleast” and “up to” are inclusive. For example, a composition comprising“at least 2.5% and up to 20% by weight of DMSO” may comprise 2.5% byweight of DMSO or 20% by weight of DMSO.

DETAILED DESCRIPTION

The present invention features veterinary compositions and methods ofusing the same. Veterinary compositions of the invention includeimidacloprid or an analogue thereof; a pyrethroid such as permethrin; afirst solvent selected from the group consisting of N-methylpyrrolidone, N-ethyl pyrrolidone and mixtures thereof; and a secondsolvent which is dimethyl sulfoxide (DMSO).

Advantageously, the present inventors have found that the veterinarycompositions of the present invention provide equivalent efficacy tocommercially available products such as Advantix® while not sufferingfrom safety problems. In addition, the compositions have surprisinglybeen found to offer storage stability advantages over commerciallyavailable products. More specifically, no crystallisation is observedeven after prolonged storage at low temperature conditions which isparticularly relevant because such temperature conditions are likely tobe encountered as a consequence of distribution across various climatezones.

The compositions of the present invention comprise imidacloprid or ananalogue thereof. Imidacloprid(N-{1-[(6-Chloro-3-pyridyl)methyl]-4,5-dihydroimidazol-2-yl}nitramide)is a neonicotinoid which acts systemically on the central nervous systemof insects. These active compounds work by causing a blockage in thenicotinergic neuronal pathway which leads to an accumulation of theneurotransmitter acetylcholine. This accumulation ultimately leads tothe paralysis and death of the insect. Imidacloprid has chemicalstructure (I) below:

Suitable imidacloprid analogues have the chemical structure (II):

wherein

R is hydrogen or an optionally substituted radically selected from thegroup consisting of acyl, alkyl, aryl, aralkyl, heteroalkyl andheteroarylakyl;

A is a monofunctional group selected from the group consisting ofhydrogen, acyl, alkyl, aryl, or a bifunctional group which is attachedto the radical Z;

E is an electron withdrawing radical;

X is —CH═ or ═N—, wherein —CH═ may be attached to the radical Z in placeof the Hydrogen atom; and

Z is a monofunctional group selected from the group consisting of alkyl,—O—R, —S—R, —N(R¹)(R²), wherein R¹ and R² may be the same or differentor Z is a bifunctional group which is attached to A or X; and

R¹ and R² are independently selected from the group consisting ofhydrogen, acyl, alkyl, aryl, aralkyl, heteroalkyl and heteroaralkyl.

The term “acyl” as used herein refers to a radical of formula —C—(O)—R′,—S—(O)—R′ or —P(O)R′₂. Examples of suitable acyl groups include alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,(alkyl)(aryl)phosphoryl, all of which may be substituted.

The term “alkyl” is used herein to refer to monovalent, divalent ortrivalent straight or branched, saturated, acyclic hydrocarbyl groups.Particular groups which may be mentioned include C₁₋₁₀ alkyl, inparticular C₁₋₄ alkyl, specifically methyl, ethyl, isopropyl, sec- ortert-butyl, all of which may be substituted.

The term “aryl” is used herein to refer to monovalent, divalent ortrivalent, aromatic, cyclic hydrocarbyl groups, such as phenyl ornaphthyl (e.g. 1-naphthyl or 2-naphthyl), in particular phenyl.

The term “aralkyl” as used herein refer to an alkyl group in which oneor more hydrogens has been replaced with an aryl group. Aralkyl whichmay be mentioned are phenylmethyl and phenethyl.

The term “heteroaryl” is used herein to refer to monovalent, divalent ortrivalent, heteroaromatic, cyclic hydrocarbyl groups additionallycontaining one or more heteroatoms independently selected from 0, S, Nand NR^(T), wherein R^(T) is preferably H or C₁-C₁₀ alkyl. Particularmention is made of heteroaryl groups having up to 10 ring atoms and, asheteroatoms, N, O and S, in particular N. Specific mention may be madeof thienyl, furyl, thiazolyl, imidazolyl, pyridyl, benzothiazolyl.

The term “heteroarylalkyl” is used herein to refer to heteroaryl groupssubstituted with one or more alkyl groups. Specific heteroarylalkylgroups which may be mentioned are heteroarylmethyl and heteroarylethylhaving up to 6 ring atoms and, as heteroatoms, N, O, S, in particular N.

As indicated above, a number of the groups defined may optionally besubstituted. Exemplary and preferred substituents include C₁₋₄ alkyl, inparticular methyl, ethyl, n- and isopropyl and n-, iso- and tert-butyl;alkoxy having preferably 1 to 4, in particular 1 or 2, carbon atoms,such as methoxy, ethoxy, n- and isopropyloxy and n-, iso- andtert-butyloxy; alkylthio having preferably 1 to 4, in particular 1 or 2,carbon atoms, such as methylthio, ethylthio, n- and isopropylthio andn-, iso- and tert-butylthio; haloalkyl having preferably 1 to 4, inparticular 1 or 2, carbon atoms and preferably 1 to 5, in particular 1to 3, halogen atoms, where the halogen atoms are identical or differentand are preferably fluorine, chlorine or bromine, in particularfluorine, such as trifluoromethyl; hydroxyl; halogen, preferablyfluorine, chlorine, bromine and iodine, in particular fluorine, chlorineand bromine; cyano; nitro; amino; monoalkyl- and dialkylamino havingpreferably 1 to 4, in particular 1 or 2, carbon atoms per alkyl group,such as methylamino, methylethylamino, n- and isopropylamino andmethyl-n-butylamino; carboxyl; carbalkoxy having preferably 2 to 4, inparticular 2 or 3, carbon atoms, such as carbomethoxy and carboethoxy;sulpho (—SO3H); alkylsulphonyl having preferably 1 to 4, in particular 1or 2, carbon atoms, such as methylsulphonyl and ethylsulphonyl;arylsulphonyl having preferably 6 or 10 aryl carbon atoms, such asphenylsulphonyl, and also heteroarylamino and heteroarylalkylamino, suchas chloropyridylamino and chloropyridylmethylamino.

Preferred examples of the substituents, A, Z, E and X are as follows.

A is preferably hydrogen and also represents optionally substitutedradicals from the group consisting of acyl, alkyl, aryl, which arepreferably as defined under R. A may alternatively be a bifunctionalgroup. In this regard, examples include optionally substituted alkylenehaving 1-4, in particular 1-2, carbon atoms, substituents which may bementioned being the substituents listed further above, where thealkylene groups may be interrupted by heteroatoms from the groupconsisting of N, O and S.

A and Z together with the atoms to which they are attached may form asaturated or unsaturated heterocyclic ring. The heterocyclic ring maycontain a further 1 or 2 identical or different heteroatoms and/orhetero groups. Preferred heteroatoms are oxygen, sulphur or nitrogen andpreferred hetero groups are N-alkyl, where the alkyl of the N-alkylgroup contains preferably 1 to 4, in particular 1 or 2, carbon atoms.Alkyl which may be mentioned are methyl, ethyl, n- and isopropyl and n-,iso- and tert-butyl. The heterocyclic ring contains 5 to 7, preferably 5or 6, ring members.

Examples of the heterocyclic ring include pyrrolidine, piperidine,piperazine, hexamethyleneimine, hexahydro-1,3,5-triazine, morpholine,which may optionally be substituted, preferably by methyl.

E may be an electron-withdrawing radical, where mention may be made inparticular of NO₂, CN, haloalkylcarbonyl, such as1,5-halo-C₁₋₄-carbonyl, in particular COCF₃.

X may be —CH═ or —N═.

Z may be optionally substituted radicals alkyl, —OR, —SR, —NRR, where Rand the substituents preferably have the meaning given above.

Z can furthermore, in addition to the ring mentioned above, form,together with the atom to which it is attached and the radical ═C(CH₃)—instead of X, a saturated or unsaturated heterocyclic ring. Theheterocyclic ring may contain a further 1 or 2 identical or differentheteroatoms and/or hetero groups. Preferred heteroatoms are oxygen,sulphur or nitrogen and preferred hetero groups are N-alkyl, where thealkyl or N-alkyl group contains preferably 1 to 4, in particular 1 or 2,carbon atoms. Alkyl which may be mentioned are methyl, ethyl, n- andisopropyl and n-, iso- and tert-butyl. The heterocyclic ring contains 5to 7, preferably 5 or 6, ring members.

Examples of the heterocyclic ring include pyrrolidine, piperidine,piperazine, hexamethyleneimine, morpholine and N-methyl-piperazine.

Preferred imidazole analogues for use in the composition of the presentinvention include the compounds of formula (III) and formula (IV) below:

Particularly suitable imidacloprid analogues include:

The imidacloprid or analogue thereof is included in the compositions ofthe present invention in an amount in the range from about 0.1% to about20% by weight, preferably in the range from about 1% to about 15% byweight, more preferably in the range from about 2.5% to about 12.5% byweight.

The compositions of the present invention further comprise a pyrethroid.A pyrethroid is an organic compound similar to the natural pyrethrinsproduced by the flowers of pyrethrums (Chrysanthemum cinerariaefoliumand C. coccineum). Pyrethroids function as neurotoxins, affecting neuralmembranes by prolonging sodium channel activation. Examples of suitablepyrethoids include acrinathrin, allethrin, bifenthrin, bioallethrin,bioallethrin S-cyclo pentenyl isomer, bioresmethrin, cycloprothrin,cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda cyhalothrin,cypermethrin, including the resolved isomers alpha-cypermethrin,beta-cypermethrin and zeta-cypermethrin, cyphenothrin, deltamethrin,empenthrin, esfenvalerate, etofenprox, fenpropathrin, fenvalerate,flucythrinate, tau-fluvalinate, flumethrin, imiprothrin,lambda-cyhalothrin, metofluthrin, permethrin, phenothrin[(1R)-trans-isomer], prallethrin, resmethrin, RU15125, silafluofen,sumithrin, tau-fluvalinate, tefluthrin, tetramethrin, tetramethrin[(1R)-isomers], tralomethrin, transfluthrin, transflumethrin. Differentpyrethroids will be suitable depending on the animal which is to betreated with the veterinary composition of the present invention and theskilled person will be familiar with appropriate pyrethroids to select.For example, permethrin is known to be toxic for cats. Preferably, thepyrethroid is selected from the group consisting of etofenprox,deltamethrin, permethrin, cyfluthrin, flumethrin, cypermethrin,cyphenothrin, fenvalerate, esfenvalerate and lambda-cyhalothrin. In oneembodiment, the pyrethroid is selected from the group consisting ofetofenprox, deltamethrin, cyfluthrin, flumethrin, cypermethrin,cyphenothrin, fenvalerate, esfenvalerate and lambda-cyhalothrin.

The veterinary compositions of the present invention comprise thepyrethroid in an amount in the range from about 0.1% to about 75% byweight. The amount of pyrethroid which is present will depend on thepyrethroid. For example, where the pyrethroid is deltamethrin, it ispreferably included in an amount in the range from about 0.1% to about20% by weight. Alternatively, where the pyrethroid is etofenprox, it ispreferably included in an amount in the range from about 0.1% to about60% by weight. Alternatively, where the pyrethroid is permethrin, it ispreferably included in an amount in the range from about 0.1% to about70% by weight. Alternatively, where the pyrethroid is flumethrin, it ispreferably included in an amount in the range from about 0.1% to about25% by weight. Alternatively, where the pyrethroid is cyfluthrin, it ispreferably included in the amount in the range from about 0.1% to about25% by weight. Alternatively, where the pyrethroid is cypermethrin, itis preferably included in an amount in the range from about 0.1% toabout 60% by weight. Alternatively, where the pyrethroid iscyphenothrin, it is preferably included in an amount in the range fromabout 0.1% to about 60% by weight. Alternatively, where the pyrethroidis fenvalerate, it is preferably included in an amount in the range fromabout 0.1% to about 60% by weight. Alternatively, where the pyrethroidis esfenvalerate, it is preferably included in an amount in the rangefrom about 0.1% to about 60% by weight. Alternatively, where thepyrethroid is lambda-cyhalothrin, it is preferably included in an amountin the range from about 0.1% to about 25% by weight.

Preferably, the compositions of the present invention comprisepermethrin. Permethrin ((3-phenoxyphenyl)methyl3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate) is aninsecticide which is known for the treatment of parasites on animals. Anadvantage of using permethrin as the pyrethroid in the veterinarycompositions of the present invention is that it is known to possess arepellancy effect. This repellancy effect is useful in preventing fleaallergy dermatitis (FAD), an immunological response to the flea salivaby preventing the fleas from actually biting the animal.

The compositions of the present invention preferably comprise permethrinin an amount in the range from about 25% to about 75% by weight,preferably about 35% to about 67.5% by weight, preferably in an amountin the range from about 40% to about 67.5% by weight, more preferably inan amount in the range from about 42.5% to about 67.5% by weight.Commercially available sources of permethrin may comprise an isomericmixture of cis-permethrin and trans-permethrin with the typicalcis:trans ratios available being 25:75, 40:60 and 80:20. It is withinthe knowledge of the skilled person to adjust the amount of permethrinincluded with the veterinary compositions of the present invention inorder to account for the particular isomeric ratio of the source ofpermethrin used.

The compositions of the present invention may comprise one or morefurther active ingredients. In one embodiment, the compositions of thepresent invention may comprise pyriproxifen. Pyriproxifen(2-[1-(4-phenoxyphenoxy)propan-2-yloxy]pyridine, CAS No. 95737-68-1) isa juvenile hormone analogue. Where present, pyriproxyfen may be includedin an amount of up to about 2% by weight.

Alternatively or in addition, in order to broaden the spectrum ofactivity, the compositions of the present invention may comprise up toabout 40% by weight, alternatively up to about 30% by weight,alternatively up to about 20% by weight of one or more veterinaryacceptable endoparasitic and exoparasitic agents. Examples of suitableagents include, but are not limited to, ivermectin, avermectin,milbemycin, methoprene, trifluron, fenoxycarb, lufenuron, cyromazine,diflubenzuron; amitraz, propoxur, cythioate, moxydectin, selamectin andisoxazolines. Where an endoparasitic agent is included within thecompositions of the present invention, it will have a systemic effectwhile the activity of the combination of the imidacloprid and thepyrethroid remains non-systemic.

In addition to the active ingredients, imidacloprid or an analoguethereof and permethrin, the balance of the compositions of the presentinvention by weight comprises a first solvent selected from the groupconsisting of NMP and N-ethylpyrrolidone (NEP) and mixtures thereof anda second solvent which is DMSO. As described above, with regard tosafety, NMP has been classified as a category 2 solvent which means thatgreat care needs to be taken when it is handled. In contrast, DMSO isclassified as a class 3 solvent by the FDA. Thus, by including DMSO asan essential component, the amount of NMP or NEP which is required hasbeen reduced and so the compositions of the present invention can bemanufactured more safely than currently available formulations whichcomprise the same active ingredients.

The present inventor has also surprisingly found that where thecompositions include this combination of solvents then the compositionscan be stored at low temperatures (i.e. about 5° C.) without anycrystallisation being observed. This is not the case with the currentlyavailable commercial products.

The avoidance of crystallisation is important in order to ensure thatthe compositions perform in the way in which is intended afterapplication to the animal. More specifically, as has been describedpreviously, while the compositions are not systemically active on theanimal to which they are applied, it is important that the formulationsremain in a liquid form for a period which is sufficiently long thatthey can penetrate through to the lower dermal layers (i.e. stratumcorneum) and hence then spread over the body of the animal. In additionto penetrating to the lower dermal layers, it is believed that spreadingof the active ingredients included within the formulations from a singleapplication locus also occurs as a consequence of dissolution in theanimal's sebum. Without wishing to be bound by theory, it is alsobelieved that, as a consequence of dissolution in the sebum, a reservoirof active ingredients is formed within the sebaceous glands which mayaccount for the long term duration of the compositions of the presentinvention. These effects cannot occur where the active ingredientscrystallise out of solution.

Furthermore, during transport of the compositions prior to sale throughvarious climate zones, it is likely that low temperatures will beencountered. In such a situation, if the compositions are prone tocrystallisation then lower efficacy will be observed when they areultimately used on an animal.

The terms “systemically active” and “systemic effect” are used herein torefer to an effect or efficacy only when intracorporeally present withinthe target pest, such as after ingestion or other administration whichresults in the presence of both active agents in the target pest. Otherthan when used in respect of an optionally present endoparasitic agent,the term does not mean having a deleterious effect when present withinthe system of a host domestic animal, it is limited to activity orefficacy when intracorporeally present within a pest.

As described above, it is essential that the compositions include atleast some DMSO. Without wishing to be bound by theory, it is believedthat the presence of the DMSO prevents the composition fromcrystallising at low temperature and only small amounts of DMSO arerequired in order to observe this change. In this regard, thecompositions of the present invention may comprise at least about 2.5%by weight of DMSO, alternatively at least about 5% by weight,alternatively at least about 7.5% by weight, alternatively at leastabout 10% by weight of DMSO. From the viewpoint of improving safety, itis advantageous to replace as much NMP as possible, while stillproviding a composition which is effective. In this regard, thecompositions of the present invention may include greater than 10% byweight, alternatively greater than 12% by weight of DMSO. The content ofDMSO is preferably less than about 97.3% by weight, preferably less thanabout 80% by weight, preferably less than about 60%, preferably lessthan about 50%, in some embodiments, less than about 45% by weight.Thus, in one embodiment, the content of DMSO may be in the range fromabout 2.5% to about 60% by weight, in one embodiment, it may be in therange from about 7.5% to about 40% by weight, alternatively in the rangefrom about 10% to about 30% by weight, alternatively in the range fromabout 15% to about 27.5% by weight, in one embodiment, in the range fromabout 17.5% to about 27.5% by weight. In some embodiments, thecompositions of the present invention include at least 2.5% but lessthan 20% by weight of DMSO. For example, a composition of the inventionmay include between (a) 2.5% and 5%, (b) 2.5% and 10%, (c) 2.5% and 15%,(d) 2.5% and 20%, (e) 5% and 10%, (f) 5% and 15%, (g) 5% and 17%, (h) 5%and 18%, (i) 5% and 19%, (j) 5% and 20%, (k) 10% and 15%, (I) 10% and17%, (m) 10% and 18%, (n) 10% and 19%, (o) 10% and 20%, (p) 15% and 17%,(q) 15% and 18%, (r) 15% and 19%, (s) 15% and 20%, (t) 17% and 18%, (u)17% and 19%, (v) 17% and 20%, (w) 18% and 19%, (x) 18% and 20%, or (y)19% and 20% by weight of DMSO. In certain embodiments, a composition ofthe present invention includes 15 to 19% by weight of DMSO. Inparticular embodiments, a composition of the present invention includesbetween 17% and 19% by weight of DMSO.

However, while including DMSO improves the safety of the compositions ofthe present invention, the inventor has surprisingly found that it isstill not possible to completely eliminate the use of NMP, NEP or amixture thereof. In this regard, while literature may suggest that DMSOmay simply be substituted for NMP, the inventor has found that if DMSOis used alone in the present compositions then the crystallisationproperties of the compositions are not suitable. More specifically, ithas been found that the active ingredients crystallise out of thesolution too quickly (i.e. before penetration to the lower dermal layershas been achieved) and so the resulting compositions suffer from lowerefficacy.

Therefore, the compositions of the present invention may comprise thefirst solvent in an amount of at least about 2.5% by weight,alternatively at least about 5% by weight, alternatively at least about7.5% by weight. From the viewpoint of improving safety, it isadvantageous to minimise the content of the first solvent to the extentthat this is possible while still maintaining efficacy. In this regard,the compositions of the present invention may include less than about27.5% by weight, preferably less than about 25% by weight of the firstsolvent. Thus, the content of the first solvent may be in the range fromabout 2.5% to about 25% by weight. In some embodiments, the compositionsof the present invention include greater than 20% by weight of the firstsolvent. For example, a composition of the present invention may includefrom (a) greater than 20% and up to 27.5%, (b) 21 to 27.5%, (c) 22 to27.5%, (d) greater than 20% and up to 25%, (e) 21 to 25%, (f) 22 to 25%,(g) greater than 20% and up to 23%, (h) 21 to 23%, or (i) 22 to 23% byweight of the first solvent. In particular embodiments, a composition ofthe present invention includes between 21 and 23% by weight of the firstsolvent. In particular embodiments, the first solvent is N-methylpyrrolidone.

The compositions of the present invention may further comprise up to 5%by weight of water (e.g., 0%, 1%, 2%, 3%, 4%, or 5% by weight).

In addition to the components already discussed, the compositions of thepresent invention may further comprise an anti-oxidant. An anti-oxidantis included for the purpose of preventing degradation and thus improvingthe stability of the compositions. Where included, an anti-oxidant maybe present in an amount of up to about 0.5% by weight (e.g., 0%, 0.05%,0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, or 0.5% by weight).Where present, an anti-oxidant is preferably included in an amount inthe range from about 0.05% to about 0.25% by weight. The skilled personwill be familiar with suitable anti-oxidants for incorporation intoveterinary compositions. Examples include phenolic anti-oxidants whichas butylated hydroxytoluene, butylated hydroxyanisole and tocopherol.

Alternatively or in addition, the compositions of the present inventionmay further comprise up to about 2% by weight of an organic acid (e.g.,0%, 0.5%, 1%, 1.5%, or 2% by weight). Preferably, where present, anorganic acid may be included in an amount in the range from about 0.05%to about 1% by weight. Suitable organic acids include all organic acidswhich are acceptable for use in veterinary and pharmaceutical products.Examples include carboxylic acids such as citric acid, tartaric acid,lactic acid, succinic acid and malic acid. Citric acid is preferred.

The compositions of the present invention may also further comprise,typically in an amount of up to about 40% by weight (e.g., 0%, 5%, 10%,15%, 20%, 25%, 30%, 35%, or 40% by weight), of one or more furtherveterinary acceptable excipients. Examples of such excipients includebut are not limited to surfactants and spreading agents. Suitablesurfactants include non-ionic surfactants, such as polyethoxylatedcastor oil, polysorbates (ethoxylated esters or partial esters ofsorbitol), polyethoxylated sorbitan monooleate, sorbitan monostearate,glycerol monostearate, polyoxystearate, alkylphenol polyglycol ethers,polyoxyethylene alkyl ethers and esters, polyoxyethylene alkylphenolsand poloxamers (polyoxyethylene-polyoxypropylene block copolymers);ampholytic surfactants such as di-sodium N-lauryl-β-imino-dipropionateor lecithin, phosphatidylcholine, alkyl betaines (e.g. cocamidopropylbetaine); anionic surfactants, such as sodium lauryl sulphate, fattyalcohol ether sulphates, mono/dialkyl polyglycol ether orthophosphoricacid ester monoethanolamine salt, sodium stearate; and cationicsurfactants such as cetyltrimethylammonium chloride,cetyltrimethylammounium bromide, octadecylamine hydrochloride. Suitablespreading agents include spreading oils such as di-2-ethylhexyl adipate,isopropyl myristate, dipropylene glycol pelargonate, cyclic and acylicsilicone oils, such as dimethicone and further co- and terpolymersthereof with ethylene oxide, propylene oxide and formaldehyde, fattyacid esters, triglycerides, fatty alcohols.

The compositions of the present invention are liquid and hence suitablefor dermal application. Preferably the compositions of the presentinvention are pour-on or spot-on formulations.

The compositions of the present invention are useful for controlling aparasite on or within an animal. Accordingly, the present inventionfurther provides a veterinary composition as defined herein, for use incontrolling a parasite on or within a warm-blooded domesticated animal.The parasites are selected from the group consisting of ectoparasites,endoparasites or both.

The animal may be a small domesticated animal such as a cat, dog,rabbit, ferret or other warm-blooded animal. The compositions of thepresent invention are particularly useful for controlling a parasite onor within a dog, particularly where the pyrethroid is permethrin.

The parasite infecting the animal to be treated may be selected from oneor more of the groups consisting of fleas, ticks, mites, lice,intestinal worms, heartworms and other internal worms and mixturesthereof. Examples of particular parasites which may be mentioned includeparasites from the order of the Anoplura e.g. Haematopinus spp.,Linognathus spp., Solenopotes spp., Pediculus spp., Pthirus spp.; fromthe order of the Mallophaga e.g. Trimenopon spp., Menopon spp.,Eomenacanthus spp., Menacanthus spp., Trichodectes spp., Felicola spp.,Damalinea spp., Bovicola spp.; from the order of the Diptera e.g. Aedesspp., Culex spp., Simulium spp., Phlebotomus spp., Chrysops spp.,Tabanus spp., Musca spp., Hydrotaea spp., Muscina spp., Haematoboscaspp., Haematobia spp., Stomoxys spp., Fannia spp., Glossina spp.,Lucilia spp., Calliphora spp., Auchmero-myia spp., Cordylobia spp.,Cochliomyia spp., Chrysomyia spp., Sarcophaga spp., Wohlfartia spp.,Gasterophilus spp., Oesteromyia spp., Oedemagena spp., Hypoderma spp.,Oestrus spp., Rhinoestrus spp., Melophagus spp., Hippobosca spp.; fromthe order of the Siphonaptera e.g. Ctenocephalides spp., Echidnophagaspp., Ceratophyllus spp., Pulex spp., Hystrichopsyllidae spp.,Ctenopsyllidae spp., Amphipsyllidae spp., from the order of theMetastigmata e.g. Hyalomma spp., Rhipicephalus spp., Boophilus spp.,Amblyomma spp., Haemaphysalis spp., Dermacentor spp., Ixodes spp., Argasspp., Ornithodorus spp., Otobius spp.; from the order of theMesostigmata e.g. Dermanyssus spp., Ornithonyssus spp., Pneumonyssusspp.; from the order of the Prostigmata e.g. Cheyletiella spp.,Psorergates spp., Myobia spp., Demodex spp., Neotrombi-cula spp.; fromthe order of the Astigmata e.g. Acarus spp., Myocoptes spp., Psoroptesspp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp.,Knemidocoptes spp., Neoknemidocoptes spp. Cytodites spp., Laminosioptesspp., from the order Ascaridida, e.g. Toxocaridae, from the orderTrichocephalida, e.g. Trichuridae, from the order Strongylida, e.g.Ancylostomatidae, Filaroididae, Metastrongylidae from the orderRhabditia, e.g. Rhabditida spp., from the order Cyclophyllidea, e.g.Taeniidea, Mesocestoides spp., Dipylidiidae, from the order Spirurida,e.g. Onchocercidae, Thelaziidae, from the order Trichurida, e.g.Capillariidae, Crenosomatidae.

When administered as a spot-on formulation, the compositions of thepresent invention are typically administered in an amount ofapproximately about 0.075 to about 0.25 ml per kg body weight of theanimal to a single locus, typically between the shoulder blades of theanimal. The characteristics of the compositions mean that they spreadfrom the single locus across the skin of the animal. As described above,without wishing to be bound by theory, this is believed to be as aconsequence of a combination of penetration to the lower dermal levelsand spreading through sebum.

The compositions of the present invention are particularly effective incontrolling both fleas and ticks. The term “controlling” as used hereinmeans eradicating or substantially reducing an existing infestation,preventing a new infestation and preventing reinfestation fromectoparasites in the environment, including by the eradication orsubstantial reduction of ectoparasites in areas habitually visited bythe animal, such as its resting place. In particular, in addition toproviding long term stability under low temperature storage conditionsi.e. in all climate zones, the compositions of the present invention aretoxicologically acceptable, dermally-friendly and provide good long-termaction of at least three to four weeks following administration of asmall volume to the skin of the animal to be treated (for example 0.1ml/kg body weight of the animal to be treated). Thus, the compositionsof the present invention are at least as effective as the currentlyavailable products in treating fleas and ticks but offer improved safetyand storage stability.

The compositions of the present invention show no crystallisation whenstored at a temperature of about 5° C. for a period of 20 days orgreater, preferably 30 days or greater, preferably 40 days or greater,preferably 50 days or greater.

The invention will now be illustrated further by reference to thefollowing examples which are in no way intended to be limiting on thescope of the invention.

EXAMPLES

Solubility studies were performed in order to identify suitablealternative solvents for NMP in the formulation of a veterinarycomposition comprising imidacloprid and permethrin. The commerciallyavailable Advantix® (from Bayer) was used as a reference against whichthe compositions were tested.

The active ingredients used were Imidacloprid (CAS 128261-41-3) andPermethrin (CAS 52645-53-1).

The solvents tested were as follows:

N-methyl pyrrolidone (CAS 872-50-4)

N-ethyl pyrrolidone (CAS 2687-91-4)

Transcutol (CAS 111-90-0)

Dowanol dmp (CAS 34590-94-8)

Glycofurol (CAS 31692-85-0)

Polyvinylpyrrolidone (CAS 9003-39-8)

Propylene carbonate (CAS 108-32-7)

Dimethyl sulfoxide (CAS 67-68-5)

G-butyrolactone (CAS 96-48-0)

n-butanol (CAS 71-36-3)

RhodiaSolv IRIS (CAS 14035-94-0)

Armid® FM PC

Details of the formulations tested are set out in Table 1 below.

Formulations 1 to 2A and A to I were formulated in 100 ml beakers to atotal volume of 70 ml and the solubility of the active ingredients inthe different solvents was assessed. 7.14 g of imidacloprid was added tothe solvent mixture followed by 35.79 g of permethrin, warmed to atemperature of approximately 45° C. so that it is a clear liquid. Themixture was vigorously stirred throughout the additions. Theformulations were then mixed for a further three hours at roomtemperature and the degree of dissolution was assessed.

Where dissolution was successful, the formulation was transferred intothree pre-labelled 20 ml vials (to a fill of greater than 75%) whichwere tightly capped with a PE-lined cap. The three vials were thenstored at 5° C., room temperature and 30° C., respectively and thesamples were monitored for crystallisation. Residual formulation wastransferred to a fourth pre-labelled 20 ml vial and kept at roomtemperature. The results obtained are presented in Table 1 below.

TABLE Advantix 1Formulations 1 2 3 4 1A 2A Reference A B C D E F G H Img/ml imidacloprid 100 100 100 100 100 100 100 100 100 100 100 100 100100 100 100 Permethrin 500 500 500 500 500 500 500 500 500 500 500 500500 500 500 500 N-MP 220 220 220 220 220 220 479 250 0 250 250 250 250250 250 0 Co-solvent Transcutol QS QS Dowanol dpm QS QS Glycofurol QS QSPVP  50 Propylene Carbonate 150 150 DMSO 244 244 110 140N-Ethylpyrrolidone 250 G-Butyrolactone 249 n-Butanol 180 100 RhodiasolvIRIS 235 100 Armid FMPC 258 QS

Results of Formulation—Including Temperature Testing at 30 C, Room Tempand 5 C.

Formulations 1 and 2 could not dissolve all of the active ingredients,imidacloprid and permethrin

Formulation 3 formed cloudy phase separation, wherein addition of PVP(Formulation 4) only delayed cloudy precipitation formation

Formulations 1A and 2A (adding Propylene Carbonate) formed cloudyprecipitation

Formulations C and E could not dissolve all of the active ingredientsbut Formulation F did work (due to addition of DMSO)

Formulations A and B worked well—went on to show best low temp 5 Cstability of any product (including Advantix)

Formulation D initially good but developed precipitate at 5 C within 24hours

Formulation G developed crystals within 24 hrs at 5 C, these continuedto grow

Both Formulations H and I developed crystal formation and growth

Advantix developed crystals on day 16 at 5 C

Formulations A and B did not develop crystals at any time point during56 days testing at 5 C, room temp or 30 C

Results

As set out in Table 1, in Formulations 1, 2, 3, 4, 1A, 2A, C and E, theactive ingredients did not dissolve properly and so these formulationswere rejected, with no further analysis based on these being carriedout. In the remaining formulations, the active ingredients weredissolved and so storage tests at 5° C., room temperature and 30° C.were performed.

While formulation D looked promising initially, a precipitate was formedafter only 24 hours storage at 5° C. indicating that such a compositionwould not be suitable due to storage problems. A similar problem wasobserved with formulations F, G, H and I.

Interestingly, the Advantix® formulation which was used as a referencefor these experiments was observed to form crystals after storage at 5°C. for 16 days indicating that this formulation suffers from long termstability problems following storage at low temperatures.

Formulations A and B showed excellent results and did not demonstrateany crystal growth after storage for 56 days at 5° C., room temperatureand 30° C. Formulation comprises a mixture of NMP and DMSO, whileformulation B comprises a mixture of NEP and DMSO.

The invention claimed is:
 1. A veterinary composition comprising: 2.5%to 12.5% by weight of imidacloprid; 35% to 67.5% by weight ofpermethrin; 0.1% to 2% by weight of pyriproxyfen; and solventsconsisting of 21% to 23% by weight of a first solvent selected from thegroup consisting of N-methyl pyrrolidone, N-ethyl pyrrolidone andmixtures thereof; and 15% to less than 20% by weight of a second solventwhich is dimethyl sulfoxide (DMSO).
 2. The veterinary compositionaccording to claim 1 which comprises 17% to 19% by weight of DMSO. 3.The veterinary composition according to claim 1 wherein the firstsolvent is N-methyl pyrrolidone.
 4. The veterinary composition accordingto claim 1 which further comprises an antioxidant in an amount in therange from about 0.05% to about 0.25% by weight.
 5. The veterinarycomposition according to claim 1 which further comprises at least oneorganic acid in an amount in the range from about 0.05% to about 1% byweight.